Transcription

Ketamine is a dissociative anesthetic which
is used in medical and veterinary practice.
Outside of those settings, it's also a popular
dissociative hallucinogen that has seen widespread
recreational use.
The effects of Ketamine very much depend on
the dose.
If you only use a small amount, it may simply
alter your perception and cause mild dissociation.
With higher doses, you can enter a K-Hole,
which we'll discuss soon, and have far more
intense dissociative experiences.
The positive effects of Ketamine include ego
death, pain relief, euphoria, lasting antidepressant
effects, spiritual experiences, out of body
experiences, full dissociation, and closed
and open eye visuals.
Among the possible negative effects are increased
heart rate, confusion, impaired motor coordination,
slurred speech, decreased heart rate and blood
pressure, nausea, vomiting, paranoia, fear,
and bladder health issues.
Just like with psychedelics, that actual experience
a user has is going to depend on their set
and setting.
A lot of people are looking for a K-Hole when
they use Ketamine.
The simplest description of a K-Hole is that
its a state of full dissociation which is
often described as an out of body experience.
It can include realistic imagery, euphoria
or fear, an inability to perceive time, and
a sense of floating through an area.
The imagery associated with a Ketamine K-Hole
is usually described as relatively bright
and complex.
There are three main routes of administration
for the drug that I'll discuss: Oral, intranasal,
and intramuscular.
When used orally, the drug lasts for 90 minutes
to 2 hours and it has an onset of 10 to 30
minutes.
When used intranasally, Ketamine usually lasts
for 45 to 60 minutes, with an onset of 5 to
15 minutes.
If you inject the substance into a muscle,
it will last for 30 to 60 minutes and have
an onset of 1 to 5 minutes.
Ketamine has multiple pharmacological actions
at a number of receptors.
Much of its action has been nailed down to
the NMDA receptor, where it functions as an
antagonist.
Ketamine can also work at D2 and opioid receptors.
Further, it appears to modulate the levels
of serotonin, dopamine, and norepinephrine
to some extent.
It's believed nearly all of the recreational
effects come from the NMDA receptor antagonism,
but some may be attributed to Ketamine working
as an agonist at kappa opioid receptors.
One of the other actions of Ketamine is found
at the muscarinic acetycholine receptor, where
it is an antagonist.
This may play a minor role in its effects,
but that's not yet known.
Ketamine is an arylcyclohexylamine, placing
it in the same group as other dissociatives
like PCP and Methoxetamine.
The drug was synthesized back in 1962 by a
Parke Davis Lab pharmacist.
Come 1965, it was found Ketamine could be
used as an anesthetic and by this same year,
it was already being used recreationally.
When the recreational use began, Ketamine
was grouped with psychedelics and classified
as a dissociative anesthetic.
In the late 1960s, the drug was widely used
for anesthesia by American soldiers in Vietnam.
And by the 1970s, Ketamine was being used
around the world as a recreational drug.
The DEA became concerned about the substance
in the early 1980s, but because it wasn't
perceived to be a widely abused drug, it was
left alone.
However, from the 1980s onward, multiple deaths
were connected to Ketamine and in 1999, the
DEA looked at it once again.
At that point, Ketamine became a Schedule
3 drug and since the 2000s, it has been made
illegal in many countries.
More recently, there's been a growing interest
in Ketamine for the treatment of depression.
A normal dose when used orally is 1 to 4 mg
per lb, which comes out to around 100 to 500
mg.
With intranasal use, the dose is .15 to 1
mg per lb, which is a total of 25 to 250 mg.
And with intramuscular use, the dose is .15
to .75 mg per lb, which is 25 to 125 mg.
Using any of the higher doses I've listed
is more likely to provide memory issues and
bring you close to anesthesia.
Whereas lower doses may be a little more psychedelic,
with less full dissociation and it may be
easier to remember the experience.
Ketamine is a Schedule 3 drug in the US and
it's illegal in many other countries, including
the UK and Canada.
Ketamine has some effects, which are usually
mild, on the cardiovascular system by increasing
or decreasing heart rate and blood pressure.
It's also capable of causing respiratory depression
as well as airway obstruction, apnea, and
other breathing-related problems which could
be dangerous or fatal.
Some of those problems can be managed by using
a lower dose and having someone around to
monitor you.
One of real concerns with Ketamine is what
it can do to your brain.
It appears to have a general negative effect
on neuronal health in the form of cell death
and impaired neuroregeneration.
Those brain issues are connected to how often
you take the drug and what doses you use.
The people most likely to end up with brain
damage are those who use Ketamine daily or
close to daily.
It's also reported that regular use, such
as multiple times per week, can result in
sustained memory impairment and depression.
So, reducing your use is wise.
Urinary tract problems like lower bladder
volume, blood in your urine, involuntary urination,
atrophy, and necrosis are are real concerns
with ketamine.
Once again, the concern is greatest with very
frequent use and high doses.
If you are using grams of Ketamine daily,
it's effectively guaranteed you will encounter
urinary tract problems.
When using Ketamine, it's good to avoid anticholinergics,
alcohol, opioids, benzodiazepines, barbiturates,
and other CNS depressants.
If you have any questions about Ketamine,
feel free to leave them in the comments section.
You can also leave them in the Reddit thread
for this video, which will be linked in the
description.
Support on Patreon is greatly appreciated,
so if you'd like to contribute, you can head
to patreon.com/thedrugclassroom.
You can connect with me on Twitter @SethAFitzgerald
and via email at thedrugclassroom@gmail.com.
If you have any topic recommendations, you
can post them in the comments section or send
them to me elsewhere.

Since it suppresses breathing much less than most other available anesthetics,[30] ketamine is used in medicine as an anesthetic; however, due to the hallucinations it may cause, it is not typically used as a primary anesthetic, although it is the anesthetic of choice when reliable ventilation equipment is not available.

The effect of ketamine on the respiratory and circulatory systems is different from that of other anesthetics. When used at anesthetic doses, it will usually stimulate rather than depress the circulatory system.[36] It is sometimes possible to perform ketamine anesthesia without protective measures to the airways.[citation needed] Ketamine is considered relatively safe because protective airway reflexes are preserved.[37]

Ketamine is used as a bronchodilator in the treatment of severe asthma.[38] However, evidence of clinical benefit is limited.[38][39]

Pain management

Ketamine may be used for postoperative pain management. Low doses of ketamine may reduce morphine use, nausea, and vomiting after surgery.[40][41]

Ketamine has similar efficacy to opioids in a hospital emergency department setting for management of acute pain and for control of procedural pain.[42]

It may also be used as an intravenous analgesic with opiates to manage otherwise intractable pain, particularly if this pain is neuropathic. It has the added benefit of counteracting spinal sensitization or wind-up phenomena experienced with chronic pain. At these doses, the psychotropic side effects are less apparent and well managed with benzodiazepines.[43] Ketamine is an analgesic that is most effective when used alongside a low-dose opioid; because, while it does have analgesic effects by itself, the doses required for adequate pain relief when it is used as the sole analgesic agent are considerably higher and far more likely to produce disorienting side effects.[43] A review article in 2013 concluded, "despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain".[44]

Low-dose ketamine is sometimes used in the treatment of complex regional pain syndrome (CRPS).[45] A 2013 systematic review found only low-quality evidence to support the use of ketamine for CRPS.[46]

Depression

Some evidence has found ketamine to be a rapid-acting antidepressant in depression, for instance in major depressive disorder, treatment-resistant depression, and bipolar depression.[47][48][49][50] It also may be effective in rapidly alleviating suicidal ideation, although based on lower quality evidence.[51][52][53] The rapid-onset antidepressant effects of ketamine were first shown in small studies in 2000 and 2006.[10] They have since been demonstrated and characterized in subsequent studies.[10] A single low, sub-anesthetic dose of ketamine given via intravenous infusion may produce antidepressant effects within four hours in people with depression.[10] These antidepressant effects persist for at least a week following a single infusion.[10][54] This is in contrast to conventional antidepressants like selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), which generally require at least several weeks for their benefits to occur and become maximal.[10] Moreover, based on the available preliminary evidence, the magnitude of the antidepressant effects of ketamine appears to be more than double that of conventional antidepressants.[10] On the basis of these findings, a 2017 review described ketamine as the single most important advance in the treatment of depression in over 50 years.[54] It has sparked interest in NMDA receptor antagonists for depression, and has shifted the direction of antidepressant research and development.[55]

Penetrating eye injury. Can increase risk of loss of eye contents, due to increased IOP.

Acute porphyria. Ketamine is considered porphyrinogenic, that is, it may provoke an attack of acute porphyria in susceptible persons.

Side effects

When administered by trained medical professionals, ketamine is generally safe for those people who are critically ill.[62] Even in these cases, there are known side effects that include one or more of the following:[63]

Central nervous system: Ketamine is traditionally avoided in people with or at risk of intracranial hypertension (ICP) due to concerns about ketamine causing increased intracranial pressure. It does not increase ICP more than opioids.[64]

At anesthetic doses, 10–20% of people experience adverse reactions that occur during emergence from anesthesia, reactions that can manifest as seriously as hallucinations and delirium.[22] These reactions may be less common in some people subpopulations, and when administered intramuscularly, and can occur up to 24 hours postoperatively; the chance of this occurring can be reduced by minimizing stimulation to the person during recovery and pretreating with a benzodiazepine, alongside a lower dose of ketamine.[22] People who experience severe reactions may require treatment with a small dose of a short- or ultrashort-acting barbiturate.[63]

Tonic-clonic movements are reported at higher anesthetic doses in greater than 10% of people.[16]

Neurological

Effects of ketamine on Zebrafish development. Green areas indicate neurons, and increasing doses of ketamine reduced growth of neurons from the spinal cord.

In 1989, psychiatry professor John Olney reported ketamine caused irreversible changes, known as Olney's lesions, in two small areas of the rat brain. However, the rat brain has significant differences in metabolism from the human brain; therefore such changes may not occur in humans.[65]

The first large-scale, longitudinal study of ketamine users found current frequent (averaging 20 days/month) ketamine users had increased depression and impaired memory by several measures, including verbal, short-term memory, and visual memory. Current infrequent (averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention, and psychological well-being tests. This suggests the infrequent use of ketamine does not cause cognitive deficits, and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.[66]

Short-term exposure of cultures of GABAergicneurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and noncell-death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of dendritic arbor in differentiated neurons. The same study also demonstrated chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal maintenance and development.[67][68]

More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time.[69] Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month.[69] A study conducted on rhesus monkeys found a 24-hour intravenous infusion of ketamine caused signs of brain damage in five-day-old but not 35-day-old animals.[70]

Some neonatal experts do not recommend the use of ketamine as an anesthetic agent in human neonates because of the potential adverse effects it may have on the developing brain. These neurodegenerative changes in early development have been seen with other drugs that share the same mechanism of action of NMDA receptor antagonism as ketamine.[71]

The acute effects of ketamine cause cognitive impairment, including reductions in vigilance, verbal fluency, short-term memory, and executive function, as well as schizophrenia-like perceptual changes.[72]

Urinary tract

A 2011 systematic review examined 110 reports of irritative urinary tract symptoms from ketamine recreational use.[73] Urinary tract symptoms have been collectively referred as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy", and they include urge incontinence, decreased bladder compliance, decreased bladder volume, detrusor overactivity, and painful blood in urine. Bilateral hydronephrosis and renal papillary necrosis have also been reported in some cases.[73][74] The pathogenesis of papillary necrosis has been investigated in mice, and mononuclear inflammatory infiltration in the renal papilla resulting from ketamine dependence has been suggested as a possible mechanism.[75]

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use correspond linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 g/day reported symptoms of the lower urinary tract.[73] Urinary tract symptoms appear to be most common in daily ketamine users who have used the drug recreationally for an extended period of time.[74] These symptoms have presented in only one case of medical use of ketamine. However, following dose reduction, the symptoms remitted.[74]

Management of these symptoms primarily involves ketamine cessation, for which compliance is low. Other treatments have been used, including antibiotics, NSAIDs, steroids, anticholinergics, and cystodistension.[73] Both hyaluronic acid instillation and combined pentosan polysulfate and ketamine cessation have been shown to provide relief in some people, but in the latter case, it is unclear whether relief resulted from ketamine cessation, administration of pentosan polysulfate, or both. Further follow-up is required to fully assess the efficacy of these treatments.[73]

Liver

In case reports of three people treated with esketamine for relief of chronic pain, liver enzyme abnormalities occurred following repeat treatment with ketamine infusions, with the liver enzyme values returning below the upper reference limit of normal range on cessation of the drug. The result suggests liver enzymes must be monitored during such treatment.[76]

Ketamine can cause a variety of urinary tract problems that are more likely to occur with heavier and/or higher dosed use, especially in those not watching for a healthy lifestyle, according to a UK study.[78][79]

Other drugs which increase blood pressure may interact with ketamine in having an additive effect on blood pressure including: stimulants, SNRI antidepressants, and MAOIs. Increase blood pressure and heart rate, palpitations, and arrhythmias may be potential effects.

Benzodiazepines may diminish the antidepressant effects of ketamine.[80] Most conventional antidepressants can likely be combined with ketamine without diminished antidepressant effectiveness or increased side effects.[80]

With a few exceptions (including interactions with the D2high receptor, nicotinic acetylcholine receptors (by metabolites), and ERα) however, these actions are far weaker than ketamine's antagonism of the NMDA receptor (see the activity table to the right).[4][113] A binding study assessed ketamine at 56 sites including neurotransmitter receptors and transporters and found that it had Ki values of >10,000 nM at all sites except the dizocilpine site of the NMDA receptor (Ki = 659 nM), indicating a minimum of 15-fold selectivity for the NMDA receptor over any other site assessed in this study.[89]

Metabolites of ketamine including dehydronorketamine, hydroxynorketamine, and norketamine have been found to act as negative allosteric modulators of the α7 nicotinic acetylcholine receptor in the KXa7R1 cell line (HEK293 cells transfected with rat nicotinic acetylcholine receptor genes) with subanesthetic and nanomolar potencies (e.g., IC50 = 55 nM for dehydronorketamine), whereas ketamine itself was inactive at the same concentrations (< 1 µM).[117] These findings suggest that metabolites may contribute importantly to the pharmacodynamics of ketamine by means other than NMDA receptor antagonism.[117]

Ketamine has been found to act as a potent partial agonist of the high-affinity state of the human and rat dopamine D2 receptors in multiple studies.[94][95][96] Its apparent potency for this action is similar to that of its NMDA receptor antagonism.[94][95][96] However, there are also contradictory data, with studies finding an affinity of ketamine of >10,000 nM for the regular human and rat D2 receptors,[89][93][118] and direct interactions with the D2 receptor are controversial.[119] Moreover, whereas D2 receptor agonists like bromocriptine are able to rapidly and powerfully suppress prolactinsecretion,[120] subanesthetic doses of ketamine have not been found to do this in humans and in fact have been found to significantly and dose-dependently increase prolactin levels.[121][122]Imaging studies have shown mixed results on inhibition of striatal [11C] raclopride binding by ketamine in humans, with some studies finding a significant decrease and others finding no such effect.[123] However, changes in [11C]raclopride binding may be due to changes in dopamine concentrations induced by ketamine rather than binding of ketamine to the D2 receptor.[123]

Ketamine and certain metabolites have been found to be possible ligands of the ERα, with relatively high affinity.[101]

Effects in the brain and the body

Antagonism of the NMDA receptor is thought to be responsible for the anesthetic, amnesic, dissociative, and hallucinogenic effects of ketamine.[107] The mechanism(s) of action for the antidepressant effects of ketamine at lower doses have yet to be fully elucidated.[124] NMDA receptor antagonism results in analgesia by preventing central sensitization in dorsal horn neurons; in other words, ketamine's actions interfere with pain transmission in the spinal cord.[16] Inhibition of nitric oxide synthase lowers the production of nitric oxide – a gasotransmitter involved in pain perception, hence further contributing to analgesia.[125]

Relationship between concentrations and effects

Drowsiness, dissociation, and psychosis-like effects (e.g., hallucinations, delirium) are reported in patients treated with ketamine starting at circulating concentrations of around 50 to 200 ng/mL (210–841 nM), while analgesia begins at levels of approximately 100 to 200 ng/mL (421–841 nM).[133][11] The typical intravenous antidepressant dosage of ketamine used to treat depression is low and results in maximal plasma concentrations of 70 to 200 ng/mL (294–841 nM).[56] Circulating concentrations of around 2,000 to 3,000 ng/mL (8,413–12,620 nM) are employed during anesthesia, and patients may start to awaken once levels of ketamine have decreased to about 500 to 1,000 ng/mL (2,103–4,207 nM).[133][11] There is wide variation in the peak concentrations of ketamine that have been reported in association with anesthesia in the literature, with values ranging from 2,211–3,447 ng/mL (9,300–14,500 nM) to as high as 22,370 ng/mL (94,100 nM).[90][94]Bioactive concentrations of ketamine are lower than total plasma levels due to plasma protein binding,[90] although plasma protein binding is relatively low with ketamine (approximately 12 to 47% protein-bound).[14] Concentrations of ketamine in the brain have been reported to be several-fold higher than in plasma.[94]

Pharmacokinetics

In medical settings, ketamine is usually injected intravenously or intramuscularly.[134] Ketamine can be started using the oral route, or people may be changed from a subcutaneous infusion once pain is controlled. Oral ketamine is easily broken down by bile acids, thus has a low bioavailability. Often, lozenges or "gummies" for sublingual or buccal absorption prepared by a compounding pharmacy are used to combat this issue. Some specialists stop the subcutaneous infusion when the first dose of oral ketamine is given. Others gradually reduce the infusion dose as the oral dose is increased.[135]

Ketamine is absorbable by intravenous, intramuscular, oral, and topical routes due to both its water and lipid solubilities.[125] When administered orally, it undergoes first-pass metabolism, where it is biotransformed in the liver by CYP3A4 (major), CYP2B6 (minor), and CYP2C9 (minor) isoenzymes into norketamine (through N-demethylation) and finally dehydronorketamine.[11] Intermediate in the biotransformation of norketamine into dehydronorketamine is the hydroxylation of norketamine into hydroxynorketamine by CYP2B6 and CYP2A6. Dehydronorketamine, followed by norketamine, is the most prevalent metabolite detected in urine.[136] As the major metabolite of ketamine, norketamine is one-third to one-fifth as potent as an anesthetic, and plasma levels of this metabolite are three times higher than ketamine following oral administration.[125][137] Bioavailability through the oral route reaches 17–20%; bioavailability through other routes are: 93% intramuscularly, 8–50% intranasally, 30% sublingually, and 30% rectally.[16][11][10] Peak plasma concentrations are reached within a minute intravenously, 5 to 15 minutes intramuscularly, and 30 minutes orally.[137] Ketamine's duration of action in a clinical setting is 30 minutes to 2 hours intramuscularly and 4 to 6 hours orally.[16]

Chemistry

Structure

In chemical structure, ketamine is an arylcyclohexylamine derivative. Ketamine is a chiral compound. Most pharmaceutical preparations of ketamine are racemic; however, some brands reportedly have (mostly undocumented) differences in their enantiomeric proportions. The more active enantiomer, esketamine (S-ketamine), is also available for medical use under the brand name Ketanest S,[138] while the less active enantiomer, arketamine (R-ketamine), has never been marketed as an enantiopure drug for clinical use.

The optical rotation of a given enantiomer of ketamine can vary between its salts and free base form. The free base form of (S)‑ketamine exhibits dextrorotation and is therefore labelled (S)‑(+)‑ketamine. However, its hydrochloride salt shows levorotation and is thus labelled (S)‑(−)‑ketamine hydrochloride. The difference originates from the conformation of the cyclohexanone ring. In both the free base and the hydrochloride, the cyclohexanone ring adopts a chair conformation, but the orientation of the substituents varies. In the free base, the o-chlorophenyl group adopts an equatorial position and the methylamino group adopts an axial position.[139] In the hydrochloride salt, the positions are reversed, with the o-chlorophenyl group axial and the methylamino group equatorial.[140] Not all salts of ketamine show different optical rotation to the free base: (S)-ketamine (R,R)-tartrate is levorotatory, like (S)‑ketamine.[141]

Detection

Ketamine may be quantitated in blood or plasma to confirm a diagnosis of poisoning in hospitalized patients, provide evidence in an impaired driving arrest or to assist in a medicolegal death investigation. Blood or plasma ketamine concentrations are usually in a range of 0.5–5.0 mg/L in persons receiving the drug therapeutically (during general anesthesia), 1–2 mg/L in those arrested for impaired driving and 3–20 mg/L in victims of acute fatal overdosage. Urine is often the preferred specimen for routine drug use monitoring purposes. The presence of norketamine, a pharmacologically-active metabolite, is useful for confirmation of ketamine ingestion.[143][144][145]

History

Medical use

Ketamine vials.

Ketamine was first synthesized in 1962 by Calvin L. Stevens, a professor of Chemistry at Wayne State University and a Parke-Davis consultant conducting research on alpha-hydroxyimine rearrangements.[146] After promising preclinical research in animals, ketamine was introduced to testing in human prisoners in 1964.[25][147] These investigations demonstrated ketamine's short duration of action and reduced behavioral toxicity made it a favorable choice over phencyclidine (PCP) as a dissociative anesthetic.[148] Following FDA approval in 1970, ketamine anesthesia was first given to American soldiers during the Vietnam War.[149]

Nonmedical use

"Just Say Neigh" T-shirts making reference to ketamine became popular in the late 2000s, parodying the Just Say No campaign and ketamine's reputation as a drug for horses.[150]

Nonmedical use of ketamine began on the West Coast of the United States in the early 1970s.[149] Early use was documented in underground literature such as The Fabulous Furry Freak Brothers. It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonautJohn Lilly'sThe Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.[151] The incidence of nonmedical ketamine use increased through the end of the century, especially in the context of raves and other parties.[152] However, its emergence as a club drug differs from other club drugs (e.g., MDMA) due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;[153] in addition, there are reports of ketamine being sold as "ecstasy".[154] The use of ketamine as part of a "postclubbing experience" has also been documented.[155] Ketamine's rise in the dance culture was rapid in Hong Kong by the end of the 1990s.[153] Before becoming a federally controlled substance in the United States in 1999, ketamine was available as diverted pharmaceutical preparations and as a pure powder sold in bulk quantities from domestic chemical supply companies.[147] Much of the current ketamine diverted for nonmedical use originates in China and India.[147]

Brand names

Ketamine is primarily sold throughout the world under the brand name Ketalar.[157][6] It is also marketed under a variety of other brand names, including Calypsol, Ketamin, Ketamina, Ketamine, Ketaminol, Ketanest, Ketaset, Tekam, and Vetalar among others.[157][6]

Esketamine is sold mainly under the brand names Ketanest and Ketanest-S.[158]

Clinics

After the publication of the NIH-run antidepressant clinical trial, clinics began opening in which the medication is given.[159] This practice is an off label use of ketamine in the United States.[159] As of 2015 there were about 60 such clinics in the US; the procedure was not covered by insurance, and people paid between $400 and $1700 out of pocket for a treatment.[160] A chain of such clinics in Australia run by Aura Medical Corporation was closed down by regulatory authorities in 2015, because the clinics' marketing was not supported by scientific research and because the clinic sent people home with ketamine and needles to administer infusions to themselves.[161]

Legal status

Australia

In Australia Ketamine is listed as a schedule 8 controlled drug under the Poisons Standard (October 2015).[162] A schedule 8 drug is outlined in the Poisons Act 1964 as "Substances which should be available for use but require restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence." [163]

Canada

In Canada, ketamine is classified as a Schedule I narcotic, since 2005.[164]

Hong Kong

In Hong Kong, as of 2000, ketamine is regulated under Schedule 1 of Hong Kong Chapter 134 Dangerous Drugs Ordinance. It can only be used legally by health professionals, for university research purposes, or with a physician's prescription.[165][166]

Taiwan

By 2002, ketamine was classified as class III in Taiwan; given the recent rise in prevalence in East Asia, however, rescheduling into class I or II is being considered.[136][167]

United Kingdom

In the United Kingdom, it became labeled a Class C drug on 1 January 2006.[136][170] On 10 December 2013 the UK Advisory Council on the Misuse of Drugs (ACMD) recommended that the government reclassify ketamine to become a Class B drug,[171] and on 12 February 2014 the Home Office announced they would follow this advice "in light of the evidence of chronic harms associated with ketamine use, including chronic bladder and other urinary tract damage".[172][173]

The UK Minister of State for Crime Prevention, Norman Baker, responding to the ACMD's advice, said the issue of its recheduling for medical and veterinary use would be addressed "separately to allow for a period of consultation".[172]

United States

Recreational use

Ketamine poured onto glass and left to dry.

Recreational use of ketamine was documented in the early 1970s in underground literature (e.g., The Fabulous Furry Freak Brothers).[175] It was used in psychiatric and other academic research through the 1970s, culminating in 1978 with the publishing of psychonautJohn Lilly's The Scientist, and Marcia Moore and Howard Alltounian's Journeys into the Bright World, which documented the unusual phenomenology of ketamine intoxication.[176] The incidence of non-medical ketamine use increased through the end of the century, especially in the context of raves and other parties.[177][178][179][180][153] Its emergence as a club drug differs from other club drugs (e.g., MDMA), however, due to its anesthetic properties (e.g., slurred speech, immobilization) at higher doses;[153] in addition, reports of ketamine being sold as "ecstasy" are common.[181] In the 1993 book E for Ecstasy[182] (about the uses of the street drug Ecstasy in the UK), the writer, activist, and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ketamine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine, and selegiline", as did a consignment of "Sitting Duck" Ecstasy tablets.[183]

The use of ketamine as part of a "post-clubbing experience" has also been documented.[184] Ketamine's rise in the dance culture was most rapid in Hong Kong by the end of the 1990s.[153]

Ketamine use as a recreational drug has been implicated in deaths globally, with more than 90 deaths in England and Wales in the years of 2005–2013.[185] They include accidental poisonings, drownings, traffic accidents, and suicides.[185] The majority of deaths were among young people.[186] This has led to increased regulation (e.g., upgrading ketamine from a Class C to a Class B banned substance in the U.K.).[187]

At subanesthetic doses – under-dosaged from a medical point of view – ketamine produces a dissociative state, characterised by a sense of detachment from one's physical body and the external world which is known as depersonalization and derealization.[190] At sufficiently high doses, users may experience what is called the "K-hole", a state of extreme dissociation with visual and auditory hallucinations.[191]John C. Lilly, Marcia Moore and D. M. Turner (amongst others) have written extensively about their own entheogenic use of, and psychonautic experiences with ketamine.[192] Turner died prematurely due to drowning during presumed unsupervised ketamine use.[193]

Slang terms

Production for recreational use has been traced to 1967, when it was referred to as "mean green" and "rockmesc".[194] Recreational names for ketamine include "Special K",[195] "K",[196][195] "Kitty", "Kallie Ziltz", "Kartáč", "Ket",[197] "K2",[196] "Vitamin K",[195][197] "Super K",[195] "Honey oil",[195][198] "Jet",[195][199] "Super acid",[195] "Mauve",[195] "Special LA coke",[195] "Purple",[195] "Cat Valium",[199] "Knod-off", "Skittles", "Blind Squid",[200] "Keller",[200] "Kelly's Day",[200] "New ecstasy",[201] "Psychedelic heroin",[201] "bump",[198] "Majestic".[202] A mixture of ketamine with cocaine is called "Calvin Klein" or "CK1".[203] In Hong Kong, where illicit use of the drug is popular, ketamine is colloquially referred to as "kai-jai".[153]

Usage

North America

According to the ongoing Monitoring the Future study conducted by University of Michigan, prevalence rates of recreational ketamine use among American secondary school students (grades 8, 10, and 12) have varied between 0.8–2.5% since 1999, with recent rates at the lower end of this range.[204] The 2006 National Survey on Drug Use and Health (NSDUH) reports a rate of 0.1% for persons ages 12 or older with the highest rate (0.2%) in those ages 18–25.[205] Further, 203,000 people are estimated to have used ketamine in 2006, and an estimated 2.3 million people used ketamine at least once in their life.[205] A total of 529 emergency department visits in 2009 were ketamine-related.[206]

In 2003, the U.S. Drug Enforcement Administration conducted Operation TKO, a probe into the quality of ketamine being imported from Mexico.[207] As a result of operation TKO, U.S. and Mexican authorities shut down the Mexico City company Laboratorios Ttokkyo, which was the biggest producer of ketamine in Mexico. According to the DEA, over 80% of ketamine seized in the United States is of Mexican origin. As of 2011, it was mostly shipped from places like India as cheap as $5/gram.[207] The World Health Organization Expert Committee on Drug Dependence, in its thirty-third report (2003),[208] recommended research into its recreational use due to growing concerns about its rising popularity in Europe, Asia, and North America.

While most of Canada sees ketamine use roughly on par with other Western nations, the Toronto region has been known as an epicentre for ketamine use in the West.[citation needed] This unusual badge was enough to attract the attention of National Geographic filmmakers for their "Drugs, Inc." television series.[citation needed]

Europe

Cases of illicit ketamine use in club venues have been observed in the Czech Republic, France, Italy, Hungary, The Netherlands and the United Kingdom.[209] Additional reports of use and dependence have been reported in Poland and Portugal.[210][211]

Australia

Australia's 2010 National Drug Strategy Household Survey report shows a prevalence of recent ketamine use of 0.3% in 2004 and 0.2% in 2007 and 2010 in persons aged 14 or older.[212]

Asia

In China, the small village of Boshe in eastern Guangdong was confirmed as a main production centre when it was raided in 2013.[213]

Established by the Hong Kong Narcotics Division of the Security Bureau, the Central Registry of Drug Abuse (CRDA) maintains a database of all the illicit drug users who have come into contact with law enforcement, treatment, health care, and social organizations. The compiled data are confidential under The Dangerous Drugs Ordinance of Hong Kong, and statistics are made freely available online on a quarterly basis.[214][215] Statistics from the CRDA show that the number of ketamine users (all ages) in Hong Kong has increased from 1605 (9.8% of total drug users) in 2000 to 5212 (37.6%) in 2009.[216] Increasing trends of ketamine use among illicit drug users under the age of 21 were also reported, rising from 36.9% of young drug users in 2000 to 84.3% in 2009.[216]

A survey conducted among school-attending Taiwanese adolescents reported prevalence rates of 0.15% in 2004, 0.18% in 2005, and 0.15% in 2006 in middle-school (grades 7 and 9) students; in Taiwanese high-school (grades 10 and 12) students, prevalence was 1.13% in 2004, 0.66% in 2005, and 0.44% in 2006.[217] From the same survey, a large portion (42.8%) of those who reported ecstasy use also reported ketamine use.[217] Ketamine was the second most used illicit drug (behind ecstasy) in absconding Taiwanese adolescents as reported by a multi-city street outreach survey.[218] In a study comparing the reporting rates between web questionnaires and paper-and-pencil questionnaires, ketamine use was reported a higher rate in the web version.[219] Urine sampling at a club in Taipei, Taiwan showed high rates of ketamine use at 47.0%; this prevalence was compared with that of detainees suspected of recreational drug use in the general public, of which 2.0% of the samples tested positive for ketamine use.[220]

Research

Russian doctor Evgeny Krupitsky has claimed to have encouraging results by using ketamine as part of a treatment for alcohol addiction which combines psychedelic and aversive techniques.[221][222] Krupitsky and Kolp summarized their work to date in 2007.[223]

Veterinary medicine

In veterinary anesthesia, ketamine is often used for its anesthetic and analgesic effects on cats,[224] dogs,[225]rabbits, rats, and other small animals.[226][227] It is highly used in induction and anesthetic maintenance in horses. It is an important part of the "rodent cocktail", a mixture of drugs used for anesthetizing rodents.[228] Veterinarians often use ketamine with sedative drugs to produce balanced anesthesia and analgesia, and as a constant-rate infusion to help prevent pain wind-up. Ketamine is used to manage pain among large animals, though it has less effect on bovines.[citation needed] It is the primary intravenous anesthetic agent used in equine surgery, often in conjunction with detomidine and thiopental, or sometimes guaifenesin.

^ abRoth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.

^ abSee Max Daly, 2014, "The Sad Demise of Nancy Lee, One of Britain's Ketamine Casualties," at Vice (online), July 23, 2014, see "Archived copy". Archived from the original on 7 June 2015. Retrieved 7 June 2015.CS1 maint: Archived copy as title (link) , accessed 7 June 2015.

^The Crown, 2013, "Drug related deaths involving ketamine in England and Wales," a report of the Mortality team, Life Events and Population Sources Division, Office for National Statistics, the Crown (U.K.), see "Archived copy". Archived from the original on 7 June 2015. Retrieved 7 June 2015.CS1 maint: Archived copy as title (link) and "Archived copy". Archived from the original on 19 June 2015. Retrieved 7 June 2015.CS1 maint: Archived copy as title (link) , accessed 7 June 2015.